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In August 2016, Luke Rosen found himself saying over and over to friends and family — really, whoever would listen, “We need a mouse.” His phrase became a hashtag, first used by those same friends and family, but quickly spreading to strangers. Even musicians and puppeteers made videos in support of Rosen’s plea, posting them across YouTube.
Rosen needed a special mouse for his daughter, Susannah. This “hero mouse,” as Rosen refers to it, would have to resemble Susannah as closely as possible. It didn’t need her dark hair, easy smile, or wide, brown eyes. Instead, it had to share her degenerative genetic neurological disorder.
Susannah, along with the handful of other children who have mutations in the KIF1A gene, officially called KIF1A-related disorder, has a brain and body that often fail her. When she tries to walk, stiffness and weakness in her legs cause her to trip and stumble. Susannah’s safest place is in bed, her head flopped on her father’s shoulder.
A hero mouse for Susannah would walk a little funny, too. By studying KIF1A mice and performing experiments on them, scientists would be able to better understand the KIF1A mutation and its effects. If they could develop treatments that reduce the mouse’s symptoms, they’d be well on their way to helping Susannah and kids like her.
Animal models are important research tools for all human diseases, but they’re especially crucial for researchers working to understand and treat the rarer ones. “If there are only 20 to 30 patients in the world, you aren’t going to get a well-rounded picture of what the disease looks like,” explains Cat Lutz, director of the Rare and Orphan Disease Center at the Jackson Laboratory (JAX). “A lot of times, the diseases are so newly identified that we don’t even have postmortem data.”
With limited patients, there can be too much symptom variation for doctors to fully understand the disease. A mouse model gives a more standardized, accurate, and complete picture. “We can breed hundreds of mice and look at what’s going on from a systems standpoint. We have more room to figure out what’s going wrong in their body,” says Lutz.
JAX breeds and sells more than 3 million lab mice each year, including many specialized strains designed to model specific diseases or conditions. Since the lab’s founding in 1929, JAX mice have contributed to countless medical advances, including organ transplants, leukemia treatments, and a treatment for spinal muscular atrophy.
“The role that JAX plays is twofold. We have great faculty who can help understand the diseases, but we also stand out as a resource for the scientific community,” Lutz explains. “There are thousands of rare diseases, and we can’t work on them all, but we can provide mice to the scientists who can.”
Rosen vividly recalls the day he received a phone call from Lutz and four other JAX scientists. The group outlined the logistics of modeling a neurodegenerative disease, explaining that the KIF1A kids needed not just one mouse strain, but four. According to what Rosen knew, this seemingly small change would place the price far out of reach for the tiny KIF1A.org foundation.
But Lutz was one step ahead.
“Just before the devastation of cost hit me, Cat said, ‘We want to do this for the families. Take the money you’ve raised and spend it on the next phase [of research].’ It was the first tangible goal our foundation met,” says Rosen, who was overwhelmed upon realizing that the mice would be paid for. “I was crying, so I’m not sure if they even heard me say thank you.”
But Rosen quickly discovered that genetically engineering the KIF1A mice is actually the easy part. Modern gene-editing technologies give scientists the ability to introduce human mutations into mouse genomes more quickly and precisely than ever before.
After creating a mouse model, scientists enter the “next phase” that Lutz mentioned — the hard part. Rob Burgess, who studies the rare Charcot-Marie-Tooth disease at JAX, says researchers often spend 10 or more years figuring out treatments: “Drug development is a lot of brute force. Sometimes you just have to throw the New York phone book at it and see if anything comes up,” he says. “There are lots of ways to cause each disease, and we may never know every single gene that can cause it.”
On a brighter note, Burgess adds that the current golden age of biotechnology, brought on by huge technological leaps forward in genetic sequencing and editing, has given scientists new ways to answer questions about genetic diseases.
“The hope is that things will fall into categories, so we can think of pathways instead of specific genes. Then you might hope to start your drug discovery on a pathway,” Burgess says. If a drug or other treatment acts on a biological pathway instead of on a specific gene’s function, it’s more likely to treat other diseases that disrupt the same pathway.
Mouse models are the key to investigating those pathways. Most diseases — including KIF1A — are too complex to be modeled in a test tube, and computer simulations aren’t yet advanced enough to model all the interactions that go on inside living creatures. Researchers need to run experiments in whole organisms to unravel biological mechanisms and test therapies effectively. Without mice, much of today’s genetic research and medical progress would stutter to a halt.
To draw comparisons between mouse models and their human counterparts, researchers need all the patient information they can get their hands on. Greg Cox, whose lab at JAX discovered the genetic cause of several rare neuromuscular diseases, emphasizes the need for improving interfaces between clinicians and basic scientists.
Clinicians can’t experiment on their patients, so they’re never able to actually prove causation. In contrast, a good mouse model allows scientists to test treatments — from drugs to gene therapies — through trial and error. “Basic scientists would love to be even more translational. We just need those clinical connections,” Cox says.
When he gets the chance to reach past clinical databases and connect with patients directly, Cox lights up. “Some of the research we do seems very theoretical, but patients are very grounding,” he says. “It’s been wonderful dealing with the patients, because then we get to know what the goal is.”
Lutz says interacting with rare disease patients has changed her perspective as well. “It’s not just always research on therapeutics that parents are concerned with. It’s also the day-to-day lives of their children,” she says. “People tend to jump straight to the cure, but sometimes it’s just about a treatment, something that improves a child’s life — that helps them see a little better, hear a little better, [or] move around.”
After dealing with so many rare diseases, Lutz sees the big picture better than most. In her eyes, technologies that help with rare diseases will also end up being the ones that lead to cures for common ones, like Parkinson’s.
“When you have a puzzle that has a million pieces, it’s pretty overwhelming. But when you have a puzzle that has a hundred pieces, you can put it together and have a better place to start,” Lutz says. “Eventually, some of the more common diseases may not seem as overwhelming.”
As for Rosen, he knows treatment for Susannah is not going to be simple. Nevertheless, he and his family are excited about their hero mouse and the team of researchers they’re working with to try to discover that cure.
“Until then, I’m urgently putting out the call to action for people to help our kids, who are quite literally in a race against time and fighting so hard every single day.”